Abdominal aortic aneurysms occur in up to 6 percent of individuals, and despite modern advances in diagnosis and treatment, mortality from aneurysm rupture remains high. The array of genetic factors that participate in the formation and evolution of abdominal aortic aneurysm (AAA) remains to be established. This application is a component of a Collaborative R01 in which Drs. Craig T. Basson, Richard B. Devereux, and M. David Tilson combine clinical and basic investigation of individuals with AAA to identify the molecular genetic pathways that initiate and modulate progression of AAA. Together, they will study patients with both familial and sporadic forms of AAA in order to identify specific gene mutations that cause AAA and which interact with autoimmune processes that may lead to aneurysm evolution. In Project 1, Dr. Basson will perform linkage analysis and positional cloning studies of large kindreds that are affected by an autosomal dominant familial form of abdominal aortic aneurysm disease without connective tissue abnormalities to identify mutated gene(s) that cause AAA. In Project 2, Dr. Devereux will study families affected by both Marfan syndrome and AAA to identify fibrillin-1 mutations and polymorphisms that predispose individuals affected by Marfan syndrome to abdominal vs thoracic aortic aneurysm formation. Finally, in Project 3, Dr. Tilson will characterize a novel aortic-specific (AAAP-40) and its homologs (ASAPs) that are frequent autoantigens in AAA patients and may contribute to autoimmune processes which participate in the AAA evolution. Dr. Basson's experience in cardiovascular molecular genetics, Dr. Devereux's experience in clinical and epidemiological aspects of cardiovascular-connective tissue disorders, and Dr. Tilson's experience in AAA genetics and vascular cell biology will combine to provide unique perspectives on the genetic etiologies and pathogenesis of AAA. Dr. Basson will provide expertise in chromosomal mapping and mutational analysis that will supplement all three projects. Dr. Devereux's expertise in clinical phenotyping and analysis of aortic aneurysms will provide a critical foundation for these projects. Dr. Tilson's expertise in cell biology and physiology of AAA will permit the integration of the genetic elements identified in these projects into novel cellular pathways that normally maintain vascular wall homeostasis but when perturbed lead to aneurysmal dilatation. Elucidation of the cellular genetic pathways that lead to AAA will lead to improvements in this condition's diagnosis and will ultimately suggest novel therapeutic targets to limit aortic dilatation prior to aneurysm formation and fatal rupture.